title: Costimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances antitumor effector function.
abstract: Adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) with high-dose interleukin-2 is a promising form of immunotherapy for stage IV melanoma having clinical response rates of 50% or more. One of the major problems preventing further success of this therapy is that the current protocols used to highly expand TIL for infusion drive CD8(+) T cells to differentiate into effector cells losing key costimulatory molecules such as CD28 and CD27. This has been associated with a lack of persistence in vivo for reasons not entirely clear. In this study, we demonstrate that while human melanoma CD8(+) TIL lost CD27 and CD28 expression during the rapid expansion for ACT, they gained expression of the alternative costimulatory molecule CD137/4-1BB, and to a lesser extent CD134/OX40. Postrapid expansion protocol (REP) TIL were found to be highly sensitive to activation-induced cell death when reactivated through the T-cell receptor with low levels of OKT3 antibody. However, coligation of 4-1BB using 2 different agonistic anti-4-1BB antibodies potently prevented activation-induced cell death of post-REP CD8(+) TIL, including those specific for melanoma antigen recognized by T cells, and facilitated even further cell expansion. This was correlated with increased levels of bcl-2 and bcl-xL together with decreased bim expression. 4-1BB costimulated post-REP TIL also expressed increased levels of the cytolytic granule proteins and exhibited enhanced cytotoxic T-cell activity against melanoma cells. Lastly, post-REP CD8(+) TIL were protected from cell death by anti-4-1BB ligation when exposed to human leukocyte antigen-matched melanoma cells. Our results indicate that 4-1BB costimulation may significantly improve TIL survival during melanoma ACT and boost antitumor cytolytic activity.
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jessica Ann
authors.initials: JA
authors.lastname: Hernandez-Chacon
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Li
authors.forename: Richard C
authors.initials: RC
authors.lastname: Wu
authors.forename: Chantale
authors.initials: C
authors.lastname: Bernatchez
authors.forename: Yijun
authors.initials: Y
authors.lastname: Wang
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weber
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Radvanyi
mesh_terms: D000818:Animals; D000961:Antilymphocyte Serum / Q000494:pharmacology / Q000627:therapeutic use; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D016853:Muromonab-CD3 / Q000494:pharmacology; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D053262:Receptors, OX40 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology* / Q000378:metabolism
chemical_list: D000961:Antilymphocyte Serum; D018106:CD28 Antigens; D016853:Muromonab-CD3; D053262:Receptors, OX40; C505714:TNFRSF9 protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9